High cholesterol diets raise the level of Low Density Lipoprotein (LDL) cholesterol in blood and produce heart attacks, thereby causing one-third of all deaths in the United States. The key factors that control LDL uptake and cholesterol synthesis are called sterol response element binding proteins, or SREBPs. My mentors, Brown and Goldstein, discovered SREBPs in 1993 and in the intervening years described how cells turn on and off SREBPs. SREBPs are controlled by two other factors, named Scap and Insig. Scap and Insig sense cholesterol levels in the cell. When cholesterol is high, Insigs block Scap and prevent SREBPs from being activated. When cholesterol is low, the blocking effect of Insigs is lost and Scap activates SREBPs so that they can turn on all of the genes needed to synthesize lipids or take up LDL cholesterol from the blood. Although all organs are capable of cholesterol synthesis and LDL uptake, the most important organs are the liver and small intestine. Our laboratory showed years ago that when SREBPs in the liver are not functioning properly it can lead to high blood cholesterol. Regulation of cholesterol in the small intestine is poorly understood. The interior lining of the intestines is made from cells called enterocytes. They are unique in that, in addition to getting cholesterol from endogenous synthesis and LDL uptake as do all other cells, they also absorb cholesterol from the diet. A large portion of lipids that end up elsewhere in the body originated in enterocytes, where they were newly synthesized or absorbed from food. Therefore, the intestine is critically important in the control of cholesterl homeostasis, and so the research aimed at understanding intestinal biology and the control of metabolism supported by the NIDDK has far-reaching implications. My recent studies were the first to look at SREBP function in enterocytes, and the results indicated that SREBPs provide key control of cholesterol in the small intestines. The aims of this proposal expands on these studies and outline a plan using genetically modified mice in which I will inactivate Insig (causin SREBP activation) or Scap (causing SREBP inactivation) in the intestine. The primary goal is to understand the function of SREBPs in the intestines by examining the consequences of turning them on or off. The second goal is to determine whether lipid synthesis in the intestines contributes to the buildup of lipids in other tissues associated with certain diseases: excess lipi in the blood, or hyperlipidemia, causes heart attacks. Excess lipid in the liver, or fatty liver disease, causes cirrhosis. Excess lipid in adipose tissue, or obesity, causes a huge number of health problems. By turning on or off SREBPs in the intestines of mice that also have hyperlipidemia, obesity, or fatty liver, we will find out if SREBPs contribute to these diseases. The ultimate goal is to determine if blocking SREBPs in the intestine can be employed to develop new drugs to combat hyperlipidemia, fatty liver, and obesity.